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Cellular and Molecular Biology

Downregulation of CBX7 induced by EZH2 upregulates FGFR3 expression to reduce sensitivity to cisplatin in bladder cancer

British Journal of Cancer volume 128, pages 232–244 (2023)Cite this article

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Abstract

Background

Cisplatin-based cytotoxic chemotherapy is considered to be the first-line therapy for advanced bladder cancer (BC), but resistance to cisplatin limits its antitumor effect. Fibroblast growth factor receptor 3 (FGFR3) has been reported to contribute to the progression and cisplatin resistance of BC. Meanwhile, chromobox protein homologue 7 (CBX7) was reported to inhibit BC progression. And our previous RNA-seq data on CBX7 (GSE185630) suggested that CBX7 might repress FGFR3, but the underlying mechanism and other cancer-related functions of CBX7 are still unknown.

Methods

Silico analysis of RNA-seq data to identify the upstream regulators and downstream target genes of CBX7. The western blot analysis, quantitative real-time PCR (RT-qPCR), chromatin immunoprecipitation (ChIP)-qPCR analysis, CCK-8 assay, and nude mice xenograft models were used to confirm the enhancer of zeste homologue (EZH2)/CBX7/ FGFR3 axis.

Results

In this study, we first showed that CBX7 is downregulated in BC. Then, we revealed that EZH2 represses CBX7 expression by increasing H3K27me3 in BC cells. Moreover, we demonstrated that CBX7 directly downregulates FGFR3 expression and sensitises BC cells to cisplatin treatment by inactivating the phosphatidylinositol 3-kinase (PI3K)-(RAC-alpha serine/threonine-protein kinase) AKT signalling pathway.

Conclusions

These results suggest that CBX7 is an ideal candidate to overcome cisplatin resistance in BC.

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Fig. 1: CBX7 is downregulated in bladder cancer and associated with hypermethylation in its promoter region.
Fig. 2: EZH2 suppresses CBX7 expression through H3K27 methylation in BC cells.
Fig. 3: CBX7 transcriptionally represses FGFR3 expression in BC cells.
Fig. 4: CBX7 impedes the bladder cancer progression partially through FGFR3.
Fig. 5: CBX7 modulates BC cell proliferation via the FGFR3–PI3K–AKT signalling pathway.
Fig. 6: The CBX7–FGFR3 axis modulates cisplatin resistance in BC cells.

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Data availability

The datasets used and/or analysed during this study are available from the corresponding authors upon reasonable request.

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Funding

This work was supported by grants from the Changsha Municipal Natural Science Foundation (No. kq2014236, BY).

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Author notes

  1. These authors contributed equally: Jiannan Ren, Haixin Yu, Wei Li.

Authors and Affiliations

  1. Department of Urology, The Second Xiangya Hospital, Central South University, 410011, Changsha, Hunan, China

    Jiannan Ren, Wei Li, Xin Jin & Bin Yan

  2. Uro-Oncology Institute of Central South University, 410011, Changsha, Hunan, China

    Jiannan Ren, Wei Li, Xin Jin & Bin Yan

  3. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China

    Haixin Yu

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Contributions

JR: methodology; WL: methodology; HY: conceptualisation; XJ: project administration, investigation, writing—original draft and writing—review and editing; BY: investigation and project administration.

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Correspondence to Xin Jin or Bin Yan.

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The study was conducted in accordance with the principles of the Declaration of Helsinki principles. It was approved by the Animal Use and Care Committees at the Second Xiangya Hospital, Central South University.

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Ren, J., Yu, H., Li, W. et al. Downregulation of CBX7 induced by EZH2 upregulates FGFR3 expression to reduce sensitivity to cisplatin in bladder cancer. Br J Cancer 128, 232–244 (2023). https://doi.org/10.1038/s41416-022-02058-0

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